Khouri Ricardo, Bafica André, Silva Maria da Purificação Pereira, Noronha Almerio, Kolb Jean-Pierre, Wietzerbin Juana, Barral Aldina, Barral-Netto Manoel, Van Weyenbergh Johan
Laboratory of Immunoregulation and Microbiology, Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador- Bahia, Brazi.
J Immunol. 2009 Feb 15;182(4):2525-31. doi: 10.4049/jimmunol.0802860.
Type I IFNs (IFN-alpha/beta) have only recently gained considerable attention as immunomodulators in nonviral infectious diseases. IFN-beta has been shown to protect, in a NO-dependent manner, against murine Old World leishmaniasis caused by Leishmania major, but data in New World leishmaniasis are lacking. We found that IFN-beta dose-dependently increases parasite burden in Leishmania amazonensis- as well as Leishmania braziliensis-infected human macrophages, independent of endogenous or exogenous NO. However, IFN-beta significantly reduced superoxide release in Leishmania-infected as well as uninfected human macrophages. This decrease in superoxide production was paralleled by a significant IFN-beta-mediated increase in superoxide dismutase 1 (SOD1) protein levels. Additionally, IFN-beta inhibition of leishmanicidal activity was mimicked by SOD1 and antagonized by either pharmacological or small interfering RNA-mediated inhibition of SOD1. Finally, pronounced SOD1 expression in situ was demonstrated in biopsies from New World cutaneous leishmaniasis patients. These findings reveal a hitherto unknown IFN-beta/SOD1 axis in Leishmania infection and suggest that inhibition of SOD-associated pathways could serve as strategy in the treatment of L. amazonensis as well as L. braziliensis infection, major human pathogens.
I型干扰素（IFN-α/β）直到最近才作为非病毒感染性疾病中的免疫调节剂受到广泛关注。IFN-β已被证明能以一种依赖一氧化氮（NO）的方式，保护小鼠免受由硕大利什曼原虫引起的旧大陆利什曼病的侵害，但关于新大陆利什曼病的数据尚缺。我们发现，IFN-β剂量依赖性地增加了被亚马逊利什曼原虫以及巴西利什曼原虫感染的人类巨噬细胞中的寄生虫负荷，且与内源性或外源性NO无关。然而，IFN-β显著降低了被利什曼原虫感染以及未感染的人类巨噬细胞中的超氧化物释放。超氧化物产生的这种减少与IFN-β介导的超氧化物歧化酶1（SOD1）蛋白水平的显著增加同时出现。此外，SOD1模拟了IFN-β对杀利什曼活性的抑制作用，而SOD1的药理学抑制或小干扰RNA介导的抑制则拮抗了这种作用。最后，在新大陆皮肤利什曼病患者的活检组织中证实了SOD1在原位的显著表达。这些发现揭示了利什曼原虫感染中一个迄今未知的IFN-β/SOD1轴，并表明抑制与SOD相关的途径可能作为治疗亚马逊利什曼原虫以及巴西利什曼原虫感染（主要的人类病原体）的一种策略。
